Wentilactone B induces G2/M phase arrest and apoptosis via the Ras/Raf/MAPK signaling pathway in human hepatoma SMMC-7721 cells

Abstract

Hepatocellular carcinoma (HCC) is generally acknowledged as the most common primary malignant tumor, and it is known to be resistant to conventional chemotherapy. Wentilactone B (WB), a tetranorditerpenoid derivative extracted from the marine algae-derived endophytic fungus Aspergillus wentii EN-48, has been shown to trigger apoptosis and inhibit metastasis in HCC cell lines. However, the mechanisms of its antitumor activity remain to be elucidated. We report here that WB could significantly induce cell cycle arrest at G2 phase and mitochondrial-related apoptosis, accompanying the accumulation of reactive oxygen species (ROS). Additionally, treatment with WB induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), but not p38 MAP kinase. Among the pathway inhibitors examined, only SP600125 (JNK inhibitor) markedly reversedWB-induced apoptosis, and only U0126 (ERK inhibitor) significantly blocked WB-triggered G2 phase arrest. We also found that WB treatment increased both Ras and Raf activation, and transfection of cells with dominant-negative Ras (RasN17) abolishedWB-induced apoptosis and G2 phase arrest in SMMC-7721 cells. Furthermore, the results of inverse docking (INVDOCK) analysis suggested that WB could bind to Ras–GTP, and the direct binding affinity was also confirmed by surface plasmon resonance (SPR). Finally, in vivo, WB suppressed tumor growth in mouse xenograft models. Taken together, these results indicate that WB induced G2/M phase arrest and apoptosis in human hepatoma SMMC-7721 cells via the Ras/Raf/ERK and Ras/Raf/JNK signaling pathways, and this agent may be a potentially useful compound for developing anticancer agents for HCC.

14-Thienyl Methylene Matrine (YYJ18), the Derivative from Matrine, Induces Apoptosis of Human Nasopharyngeal Carcinoma Cells by Targeting MAPK and PI3K/Akt Pathways <b><i>in Vitro</i></b>

“…MAPKs mainly consists of ERK1/2, c-Jun N-terminal kinases (JNKs) and p38 MAPKs. It has been confirmed that inactivation of ERK1/2 and activation of p38 are involved in triggering mitochondrial-mediated apoptosis in cancer cells [25,26]. In accordance with these findings, we here found that YYJ18 inhibited phosphorylation of ERK1/2 in CNE2 cells in a dose- and time-dependent manner.…”

Wentilactone A as a novel potential antitumor agent induces apoptosis and G2/M arrest of human lung carcinoma cells, and is mediated by HRas-GTP accumulation to excessively activate the Ras/Raf/ERK/p53-p21 pathway

“…13, 14, 15 We report here that EN-48-56, known as Wentilactone A (WA), exerts a significantly inhibitory effect on the lung carcinoma cell lines NCI-H460 and NCI-H446 without markedly inhibiting the proliferation of normal HUVECs. Furthermore, WA has the opposite molecular mechanism to EGFR inhibitors.…”

Avian blastoderm dormancy arrests cells in G 2 and suppresses apoptosis

“…The resultant increase in the proportion of cells arrested at the G 2 /M phase could promote either cell death or survival. For example, in some types of cancer cells, the cell cycle is arrested at G 2 /M phase in response to insults from anticancer drugs (54, 55). In the previous study, the antioxidants were used to protect blastoderm cells from peroxidative degradation during cold storage indicating that oxidative stress during dormancy could cause DNA double‐strand breaks, which could be critical to cell cycle arrest in blastoderm cells (56).…”